PROJECT SUMMARY The proposed R03 Small Grant Program for NHLBI K08 Recipients will enable my further development into an established and independent researcher with expertise on elucidating the mechanisms of cognitive decline in atrial fibrillation (AF) and enable me to understand the vascular changes in the blood vessels and brain due to AF. I am a clinical cardiologist, cardiac electrophysiologist, as well as an experienced basic and translational researcher whose long-term goal is to understand the electrophysiologic causes of AF and to develop new therapies for the treatment of cognitive and vascular dysfunction due to AF. I have a long-standing, productive relationship with my mentor, Dr. Steven Marx, an experienced ion channel researcher, with whom I published a novel mouse model, transgenic mice expressing human F1759A-NaV1.5 channels crossed with mice expressing reverse tet-transactivator (rtTA) protein, which exhibit spontaneous and sustained AF. We have demonstrated that these mice, akin to patients with AF, develop cognitive impairment. We propose to study whether increasing AF burden is associated with vascular dysfunction and if AF induced cognitive dysfunction is reversible with reduction of AF burden. I have arranged a multidisciplinary board of established investigators (Dr. Scott Small and Dr. Mu Yang, neurobiologists at Columbia University), to help me attain the goals of (1) comprehensive cognitive training to phenotype a mouse model of cognitive impairment due to AF, (2) acquiring skills in molecular cardiology and neurobiology to study possible therapies to reverse cognitive dysfunction, and (3) understanding the mechanisms in which AF alters brain vascularization. I plan to use data and skills acquired during this award to develop new therapies to treat cognitive dysfunction due to AF and obtain the data necessary for an R01 submission.